Autoimmune diseases such as rheumatoid arthritis (RA) are currently considered to be due to a complex interplay of host genetics with environmental triggering agents, which include infectious agents bacteria, viruses or mycoplasms. The overall goals of this project are to determine how microbial products such as superantigens (SAgs) might interact with RA MHC-susceptibility alleles to drive a type 1 inflammatory cytokine profile that might trigger active disease in the human host. As a model we will use the newly developed murine class II knockout mice that display various human MHC molecules that predispose to development of collagen arthritis in mice. Mice expressing these molecules will be tested for their cytokine profiles in response to in vivo exposure to the mycoplasma SAg, MAM and other bacterial SAgs using RT PCR and ELISA methodologies. We shall also investigate the mechanisms of any differences seen including the potential role of MHC binding, cell type, role of co-stimulatory molecules, and region of the SAg molecule responsible. Also we will investigate the pathogenetic effects of M. arthritidis in these "humanized" mice and determine strategies to overcome the effect of the superantigen MAM in initiating disease pathogenesis by modification of the cytokine milieu.